Two million Americans suffer a moderate to severe traumatic brain injury (TBI) each year. In addition, current military action is resulting in a large spike in the number of additional TBI cases. These injuries produce enduring disabilities that include cognitive, sensory, motor and emotional impairments. The associated health care costs from these injuries can be staggering. Confounding this major public health issue is the fact that currently there are no pharmacological treatment options for patients who have suffered a TBI. One potential cause of these failures is the lack of preclinical assessment of dosing factors (e.g., treatment windows, dose responses, and mechanism studies);in addition, preclinical studies are rarely performed in animals over 4-5 months of age. We have recently demonstrated that administration of nicotinamide, vitamin B3 (B3), following cortical contusion injury (CCI) and fluid percussion injury (FPI) resulted in a significant improvement in the recovery of sensorimotor and cognitive function, as well as in a reduction of many of the secondary pathophysiological changes that occur following injury (e.g., neurodegeneration, edema formation and reactive gliosis). However, when B3 was investigated in middle-aged (14 month old) rats following CCI, we found that the preclinical effectiveness observed in the young rats did not occur in the middle-aged rats. This is a unique and troubling finding because few studies, if any, have addressed the potential preclinical efficacy of novel therapies in the middle-age or aged rodent populations. This age range would account for a large number of TBI patients in the clinical setting. If the treatment looses efficacy in the aged population, then the clinical trial might be more likely to fail. Thus, the primary objectives of this proposal are aimed at the continued examination of B3 in aged rats following TBI. The specific aims of this study are to: 1) Determine the age window at which B3 treatment looses efficacy following TBI in rats;2) Determine the effect of B3 treatment on NAD/NADH metabolism following TBI at different age points.;3) Evaluate the preclinical efficacy of sustained infusion of B3 in middle-aged rats (14-month old);4) Compare B3 treatment following bilateral frontal CCI to treatment with progesterone (Prog) (currently in Phase II trials and has been shown to be effective in aged rats) and to the combination of both in middle-aged rats. By examining many of these clinically relevant factors (e.g., dosing regimens, long-term behavioral outcomes, and potential mechanisms) in aged subjects, we hope to build a strong case for the potential translation of B3 into clinical trials. It is also hoped that these investigations will shed light on our initial findings demonstrating reduced efficacy with B3 therapy in middle- aged rodents. PUBLIC HEALTH RELEVANCE: Two million Americans suffer a moderate to severe traumatic brain injury (TBI) each year which can produce enduring disabilities that include cognitive, sensory, motor and emotional impairments. The associated health care costs from these injuries are staggering for the families and the general public. It is hoped that the research included in this proposal will help offset this major public health crisis by helping to identify a potential therapy for TBI.